Aberrant liver sirtuin 1 (SIRT1), a mammalian NAD þ-dependent protein deacetylase, is implicated in the pathogenesis of alcoholic liver disease (ALD). However, the role of intestinal SIRT1 in ALD is presently unknown. This study investigated the involvement of intestine-specific SIRT1 in ethanol-induced liver dysfunction in mice. Ethanol feeding studies were performed on knockout mice with intestinal-specific SIRT1 deletion [SIRT1i knockout (KO)] and flox control [wild-type (WT)] mice with a chroniceplusbinge ethanol feeding protocol. After ethanol administration, hepatic inflammation and liver injury were substantially attenuated in the SIRT1iKO mice compared with the WT mice, suggesting that intestinal SIRT1 played a detrimental role in the ethanol-induced liver injury. Mechanistically, the hepatic protective effect of intestinal SIRT1 deficiency was attributable to ameliorated dysfunctional iron metabolism, increased hepatic glutathione contents, and attenuated lipid peroxidation, along with inhibition of a panel of genes implicated in the ferroptosis process in the livers of ethanol-fed mice. This study demonstrates that ablation of intestinal SIRT1 protected mice from the ethanol-induced inflammation and liver damage. The protective effects of intestinal SIRT1 deficiency are mediated, at least partially, by mitigating hepatic ferroptosis. Targeting intestinal SIRT1 or dampening hepatic ferroptosis signaling may have therapeutic potential for ALD in humans.

Background: Alcohol-associated liver disease (ALD) is caused by chronic use of alcohol and ranges from hepatic steatosis to fibrosis and cirrhosis. Bile acids are physiological detergents that also regulate hepatic glucose and lipid homeostasis by binding to several receptors. One such receptor, Takeda G protein–coupled receptor 5 (TGR5), may represent a therapeutic target for ALD. Here, we used a chronic 10-day + binge ethanol-feeding model in mice to study the role of TGR5 in alcohol-induced liver injury. Methods: Female C57BL/6J wild-type mice and Tgr5 −/− mice were pair-fed Lieber-DeCarli liquid diet with ethanol (5% v/v) or isocaloric control diet for 10 days followed by a gavage of 5% ethanol or isocaloric maltose control, respectively, to represent a binge-drinking episode. Tissues were harvested 9 hours following the binge, and metabolic phenotypes were characterized through examination of liver, adipose, and brain mechanistic pathways. Results: Tgr5 −/− mice were protected from alcohol-induced accumulation of hepatic triglycerides. Interestingly, liver and serum levels of Fgf21 were significantly increased during ethanol feeding in Tgr5 −/− mice, as was phosphorylation of Stat3. Parallel to Fgf21 levels, increased leptin gene expression in white adipose tissue and increased leptin receptor in liver were detected in Tgr5 −/− mice fed ethanol diet. Adipocyte lipase gene expression was significantly increased in Tgr5 −/− mice regardless of diet, whereas adipose browning markers were also increased in ethanol-fed Tgr5 −/− mice, indicating potential for enhanced white adipose metabolism. Lastly, hypothalamic mRNA targets of leptin, involved in the regulation of food intake, were significantly increased in Tgr5 −/− mice fed ethanol diet. Conclusions: Tgr5 −/− mice are protected from ethanol-induced liver damage and lipid accumulation. Alterations in lipid uptake and Fgf21 signaling, and enhanced metabolic activity of white adipose tissue, may mediate these effects.

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Background Progression of fatty liver disease to NASH/fibrosis is a major health concern. Bile acids regulate metabolic homeostasis and inflammation in the liver and gut via the activation of nuclear farnesoid‐X‐receptor (Fxr) and the membrane G protein‐coupled bile acid receptor 1 (Gpbar1, aka Tgr5). Tgr5 is expressed in the gut and skeletal muscle, and in cholangiocytes and Kupffer cells of the liver. Activation of Tgr5 reduces inflammation through suppression of NFκB. Tgr5 also induces GLP‐1 secretion from enterocytes to improve insulin sensitivity. Here, we fed Tgr5‐/‐ mice a high fat, high fructose, and high sucrose diet to test the hypothesis that lack of Tgr5 would exacerbate the progression from fatty liver to NASH/fibrosis. Methods Female C57Bl/6J control wild type mice (WT) and Tgr5 knockout mice (Tgr5‐/‐) were fed a high fat (40% kcal), high fructose diet + 20% sucrose water (HFS) for 20 weeks. Metabolic phenotypes were characterized through examination of lipid and cholesterol metabolism pathways, and fibrosis and inflammation pathways. Results Tgr5‐/‐ mice fed HFS were more glucose intolerant compared to WT mice, despite gaining the same amount of weight. Tgr5‐/‐ mice fed HFS accumulated significantly more hepatic cholesterol and triglycerides compared to WT mice on the same diet, and gene expression of Acc and Fasn were significantly upregulated. Surprisingly, hepatic expression of genes involved in inflammation and fibrosis were significantly reduced in Tgr5‐/‐ mice fed HFS diet. Tgr‐/‐mice had significantly reduced expression of Col1a1, Col1a2, Tgfb, and Sma. Tgr5‐/‐ also had significantly reduced liver hydroxyproline, a measure of collagen production. Liver fibrosis is partly mediated through serotonin signaling. Tgr5‐/‐mice had significantly reduced expression of Maoa and the serotonin receptors Htr2a and Htr2b, which may have protected against the development of liver fibrosis in these mice. Conclusion Altered serotonin metabolism may protect Tgr5‐/‐ mice from the progression of steatosis to NASH/fibrosis induced by a high fat, high sugar diet.

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